The primary goal of this proposal is to probe the neural mechanism of the effect of endogenous opioid blockade on impulsive choice in methamphetamine (MA) abusers. We propose a randomized placebo- controlled study of the effect of extended-release NTX on delay discounting and its neural substrate in this population. Recently abstinent MA users recruited from addiction treatment centers and the community in Portland, Oregon will be assessed at baseline and 30-days following randomization using fMRI and delay discounting task. We will also collect weekly urine drug screens and surveys at baseline and 30-days to monitor participant safety and explore the effects of NTX on MA relapse and HIV risk behaviors. In Aim 1, we determine the neural basis of impulsive choice in HIV-infected MA users. We hypothesize that activity (a) in ventral striatum (VS) and ventrolateral prefrontal cortex (VLPFC) will scale with magnitude of reward, (b) in anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) with length of delay and (c) in anterior insula and the inferior parietal lobule (IPL) with the process of making a decision. In Aim 2, we assess the effect of endogenous opioid blockade on impulsivity and its neural substrate. We hypothesize that subjects randomized to NTX will show decreased impulsivity (preference for immediate rewards) from baseline compared to those randomized to placebo (hypothesis 2.1), and that subjects with the greatest decrements in impulsivity will exhibit decreased cerebral response to reward magnitude in VS and VLPFC and decreased response to length of delay in ACC and DLPFC. These effects will be more pronounced in the NTX group (Hypothesis 2.2). The proposed work will provide the first evidence for the effect of endogenous opioid blockade on risky decision-making in MA users. Collection of behavioral data also allows for exploratory analyses to assess associations between risky decision-making and risky behaviors and inform power estimates for medication-assisted interventions. Such treatments have the potential to advance the National HIV/AIDS Strategy goal of reducing HIV transmission. PUBLIC HEALTH RELEVANCE: We propose a randomized placebo-controlled study of the effect of extended-release naltrexone on impulsive decision making in methamphetamines users. Cortical activation and impulsivity will be assessed using fMRI and delay discounting task. We will assess the effect of endogenous opioid blockade with naltrexone on measures of impulsivity.